Method for treating or preventing arteriosclerosis

ABSTRACT

Novel isoxazolidinedione derivatives of the formula (I) ##STR1## wherein R is an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group, an optionally substituted condensed heterocyclic group or a group of the formula ##STR2## R 4  is a hydrogen atom, a lower alkyl or a hydroxy; R 5  is a lower alkyl optionally substituted by hydroxy; and P and Q are each a hydrogen atom or P and Q together form a bond, and pharmaceutically acceptable salts thereof. Said novel isoxazolidinedione derivatives and pharmaceutically acceptable salts thereof have superior hypoglycemic and hypolipidemic actions and are useful for the treatment of diabetes and the complications thereof, as well as therapeutic agents for related diseases such as hyperlipidemia.

This application is a divisional of Ser. No. 08/522,264 filed Aug. 25,1995 now U.S. Pat. No. 5,728,720 which is a 371 application ofPCT/JP94/02233 filed Dec. 26, 1994.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel isoxazolidinedione derivatives.More particularly, the present invention relates to novelisoxazolidinedione derivatives which have hypoglycemic action andhypolipidemic action, and are useful as therapeutic agents for diabetesand the complications thereof, and as therapeutic agents for the relateddiseases such as hyperlipidema.

2. Description of Related Art

In general, the treatment of non-insulin-dependent diabetes mellitus(NIDDM) involves a combination of alimentotherapy, kinesitherapy, andadministration of insulin or oral hypoglycemic agents. As the oralhypoglycemic agents, there are currently known sulfonylureas such astolbutamide, chlorpropamide, acetohexamide, glibenclamide and tolazamideand biguanides such as phenformin, buformin and metformin.

While the sulfonylureas have strong hypoglycemic action, they sometimesinduce severe and prolonged hypoglycemia, and chronic use thereof mayimpair their effectiveness. In addition, the biguanides frequentlyinduce severe lactic acidosis. For these reasons, the use of thesemedications has required considerable attention.

Japanese Patent Unexamined Publication No. 85372/1988 corresponding toU.S. Pat. No. 4,572,912 teaches that thiazolidinedione derivatives suchas 5- 4-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy!benzyl!-2,4-thiazolidinedione!have hypoglycemic action, and Japanese Patent Unexamined Publication No.51189/1985 corresponding to U.S. Pat. No. 4,572,912 teaches thatthiazolidinedione derivatives such as (±)-5-4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl!-2,4-thiazolidinedione!have hypoglycemic action. It has been also taught that oxazolidinedionederivatives such as 5- 4-2-(2-phenyl-5-methyloxazol-4-yl)ethoxy!benzyl!-2,4-oxazolidinedione!described in Japanese Patent Unexamined Publication No. 170478/1991corresponding to U.S. Pat No. 5,498,621 and 5- 4- 2-N-(2-benzoxazolyl)-N-methyl!amino-ethoxy!benzyl!-2,4-oxazolidinedione!described in W092/02520 corresponding to U.S. Pat. No. 5,391,565 possesshypoglycemic action and cholesterol lowering action.

However, these compounds are not necessarily satisfactory in terms ofactivity, and the use thereof rather causes anxiety when their sideeffects (e.g. toxicity) are taken into consideration. These publicationsdo not include a description suggesting an isoxazolidinedione derivativesuch as the compounds of the present invention.

SUMMARY OF THE INVENTION

The present inventors have conducted intensive studies in an effort toprovide a compound effective as a therapeutic drug for diabetes, thecomplications thereof and hyperlipidemia, and found novel low toxicisoxazolidinedione derivatives having superior hypoglycemic action andhypolipidemic action, which resulted in the completion of the invention.

Accordingly, the present invention relates to novel isoxazolidinedionederivatives of the following (1) to (14). (1) Novel isoxazolidinedionederivatives of the formula (I) ##STR3## wherein R is an optionallysubstituted aromatic hydrocarbon, an optionally substituted alicyclichydrocarbon, an optionally substituted heterocyclic group, an optionallysubstituted condensed heterocyclic group or a group of the formula##STR4## wherein R₁ is an optionally substituted aromatic hydrocarbon,an optionally substituted alicyclic hydrocarbon, an optionallysubstituted heterocyclic group or an optionally substituted condensedheterocyclic group, R₂ and R₃ are the same or different and each is ahydrogen atom or a lower alkyl, and X is an oxygen atom, a sulfur atomor a secondary amino;

R₄ is a hydrogen atom, a lower alkyl or a hydroxy;

R₅ is a lower alkyl optionally substituted by hydroxy; and

P and Q are each a hydrogen atom or P and Q together form a bond, andpharmaceutically acceptable salts thereof.

(2) The novel isoxazolidinedione derivatives of the above (1) wherein R₄is a hydrogen atom and R₅ is a lower alkyl, and pharmaceuticallyacceptable salts thereof.

(3) The novel isoxazolidinedione derivatives of the above (2) wherein Ris an optionally substituted phenyl, an optionally substituted 5- or6-membered aromatic heterocyclic group having 1 or 2 hetero atomsselected from sulfur atom, oxygen atom and nitrogen atom, or anoptionally substituted condensed aromatic heterocyclic group whereinsuch aromatic heterocyclic ring and a benzene ring are condensed, andpharmaceutically acceptable salts thereof.

(4) The novel isoxazolidinedione derivatives of the above (3) wherein Ris a phenyl, a 5- or 6-membered aromatic heterocyclic group having oneor two hetero atoms selected from sulfur atom, oxygen atom and nitrogenatom, or a condensed aromatic heterocyclic group wherein such aromaticheterocyclic ring and a benzene ring are condensed, and pharmaceuticallyacceptable salts thereof.

(5) The novel isoxazolidinedione derivatives of the above (3) wherein Ris a phenyl, or a condensed aromatic heterocyclic group wherein abenzene ring and a 5- or 6-membered heterocyclic group having sulfuratom are condensed, and pharmaceutically acceptable salts thereof.

(6) The novel isoxazolidinedione derivatives of the above (2) wherein Ris a phenyl, a benzothienyl or 1-methyl-1-(2-pyridylthio)methyl, andpharmaceutically acceptable salts thereof.

(7) The novel isoxazolidinedione derivatives of the above (2) wherein Ris a phenyl, and pharmaceutically acceptable salts thereof.

(8) The novel isoxazolidinedione derivatives of the above (2) wherein Ris a group of the formula ##STR5## and pharmaceutically acceptable saltsthereof.

(9) The novel isoxazolidinedione derivatives of the above (8) wherein R₁is an optionally substituted phenyl or an optionally substituted 5- or6-membered aromatic heterocyclic group having one or two hetero atomsselected from sulfur atom, oxygen atom and nitrogen atom, andpharmaceutically acceptable salts thereof.

(10) The novel isoxazolidinedione derivatives of the above (8) whereinR₁ is a 5- or 6-membered aromatic heterocyclic group having one or twohetero atoms selected from sulfur atom, oxygen atom and nitrogen atom,and pharmaceutically acceptable salts thereof.

(11) The novel isoxazolidinedione derivatives of the above (8) whereinR₁ is a 5- or 6-membered aromatic heterocyclic group having nitrogenatom, and pharmaceutically acceptable salts thereof.

(12) The novel isoxazolidinedione derivatives of the above (8) whereinR₁ is pyridyl, and pharmaceutically acceptable salts thereof.

(13) The novel isoxazolidinedione derivative of the above (1) which isselected from the group of

4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzyl!-3,5-isoxazolidinedione;

4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzylidene!-3,5-isoxazolidinedione;

4- 4-2-(2-benzothienyl-5-methyl-4-oxazolyl)ethoxy!benzyl!-3,5-isoxazolidinedione;and

4- 4- 2- 5-methyl-2-(2-pyridylthio)ethyl!-4-oxazolyl!ethoxy!benzyl!-3,5-isoxazolidinedione;and pharmaceutically acceptable salts thereof.

(14) Pharmaceutical compositions comprising the novel isoxazolidinedionederivative of the above (1) or a pharmaceutically acceptable saltthereof, and a carrier.

(15) Pharmaceutical compositions of the above (14) which are agents forthe prevention and treatment of diabetes.

(16) Pharmaceutical compositions of the above (14) which are agents forthe prevention and treatment of hyperlipidemia.

(17) Pharmaceutical compositions of the above (14) which are agents forpreventing arteriosclerosis.

As used here in the present specification, "aromatic hydrocarbon" meansphenyl, biphenyl, naphthyl and the like. It may be aralkyl such asbenzyl, with preference given to phenyl.

"Alicyclic hydrocarbon" means that having 3 to 7 carbon atoms, and isexemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopropenyl, cyclobutenyl, cyclobutadienyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl and cycloheptadienyl. Preferred is alicyclic hydrocarbonhaving 5 to 7 carbon atoms, such as cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl and cycloheptadienyl, with preferencegiven to cyclopentyl and cyclohexyl.

"Heterocyclic group" is a 5-or 6-membered heterocyclic group, preferablyaromatic heterocyclic group having, as an atom constituting the ringbesides carbon atom, 1 to 3, preferably 1 or 2, hetero atoms selectedfrom nitrogen atom, oxygen atom and sulfur atom. Specific examplesinclude thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,dithiazolyl, dioxolanyl, dithiolyl, pyrrolidinyl, dithiadiazinyl,thiadiazinyl, morpholinyl, oxazinyl, thiazinyl, piperazinyl,pyperidinyl, pyranyl and thiopyranyl, with preference given to thienyl,furyl, pyrrolyl, imidazolyl, pyridyl and pyrimidinyl, and particularpreference given to pyridyl, pyrimidinyl and imidazolyl.

"Condensed heterocyclic group" means a ring wherein 5- or 6-memberedheterocyclic groups, preferably aromatic heterocyclic groups having, asan atom constituting the ring besides carbon atom, 1 to 3, preferably 1or 2, hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom have been condensed, or a ring wherein such heterocyclic group,preferably aromatic heterocyclic group and a 4- to 6-membered aromatichydrocarbon ring, preferably phenyl, have been condensed. Specificexamples include furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl,thienothiazolyl, thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl,pyrrolopyrrolyl, cyclopentathienyl, thienothienyl, oxadiazolopyrazinyl,benzofurazanyl, thiadiazolopyridinyl, triazolothiazinyl,triazolopyrimidinyl, triazolopyridinyl, benzotriazolyl,oxazolopyrimidinyl, oxazolopyridinyl, benzoxazolyl, thiazolopyridazinyl,thiazolopyrimidinyl, benzoisothiazolyl, benzothiazolyl,pyrazolotriazinyl, pyrazolothiazinyl, imidazopyrazinyl, purinyl,pyrazolopyridazinyl, pyrazolopyriminidyl, imidazopyridinyl,pyranopyrazolyl, benzimidazolyl, indazolyl, benzoxathiolyl,benzodioxalyl, dithioropyrimidinyl, benzodithiolyl, indolidinyl,indolyl, isoindolyl, furopyrimidinyl, furopyridinyl, benzofuranyl,isobenzofuranyl, thienopyrazinyl, thienopyrimidinyl, thienodioxynyl,thienopyridinyl, benzothienyl, isobenzothienyl, cyclopentaoxazinyl,cyclopentafuranyl, benzothiadiazinyl, benzotriazinyl, pyridoxazinyl,benzoxazinyl, pyrimidothiazinyl, benzothiazinyl, pyrimidopyridazinyl,pyrimidopyrimidinyl, pyridopyridazinyl, pyridopyrimidinyl, cinnolinyl,quinazolinyl, quinoxalinyl, benzoxathiinyl, benzodioxynyl,benzodithiinyl, naphthylidinyl, isoquinolinyl, quinolinyl, benzopyranyl,benzothiopyranyl, chromanyl, isochromanyl and indolinyl, with preferencegiven to benzoxazolyl, benzoisothiazolyl, benzothiazolyl,benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxalyl,benzodithiolyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzothienyl, isobenzothienyl, benzothiadiazinyl, benzotriazinyl,benzoxazinyl, benzothiazinyl, cinnolinyl, quinazolinyl, quinoxalinyl,benzoxathiinyl, benzodioxynyl, benzodithiinyl, isoquinolinyl,quinolinyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromanyl andindolinyl, and particular preference given to indolyl, isoindolyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl,isoquinolinyl and quinolinyl.

"Lower" means that the number of the carbon atoms constituting the groupis 1 to 6, preferably 1 to 4.

"Lower alkyl" means alkyl having 1 to 6 carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and neohexyl.Preferred is alkyl having 1 to 4 carbon atoms such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, withparticular preference given to methyl.

"Optionally substituted" means that the group may be substituted by 1 to3 same or different substituents. Examples of the substituent includelower alkyl such as methyl, ethyl, propyl, butyl and tert-butyl; loweralkoxy such as methoxy, ethoxy, propoxy, butoxy and tert-butoxy; halogenatom; nitro; cyano; hydroxy; acyl such as formyl, acetyl, propionyl,butyryl, isobutyryl, benzoyl and naphthoyl; acyloxy such as formyloxy,acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and benzoyloxy;aralkyloxy such as benzyloxy, phenetyloxy and phenylpropyloxy; mercapto;alkylthio such as methylthio, ethylthio, propylthio, butoxythio,isobutoxythio and tert-butoxythio; amino; alkylamino such asmethylamino, ethylamino, propylamino, isopropylamino and butylamino;dialkylamino such as dimethylamino, diethylamino, dipropylamino,diisopropylamino and dibutylamino; alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl and tert-butoxycarbonyl; amide; trifluoromethyl;phospholyl; sulfonyl; sulfonyloxy; sulfamoyl; alkylphosphonamide such asmethylphosphonamide, ethylphosphonamide, propylphosphonamide andisopropylphosphonamide; methylenedioxy; alkoxyphosphoryl such asmethoxyphosphoryl, ethoxyphosphoryl, propoxyphosphoryl andisopropoxyphosphoryl; alkylsulfonyl such as methylsulfonyl,ethylsulfonyl, propylsulfonyl, butylsulfonyl and tert-butylsulfonyl; andalkylsulfonylamino such as methylsulfonylamino, ethylsulfonylamino,propylsulfonylamino, butylsulfonylamino and tert-butylsulfonylamino.Preferred are hydroxy, lower alkyl, lower alkoxy, aralkyloxy, mercapto,lower alkylthio, nitro, halogen atom, trifluoromethyl, amino,dialkylamino, alkylamino, acyl, cyano, carbamoyl, acyloxy, sulfonyl,carboxyl and alkoxycarbonyl, with particular preference given tohydroxy, lower alkyl and lower alkoxy.

"Pharmaceutically acceptable salt" may be any as long as it forms anon-toxic salt with a novel isoxazolidinedione derivative of theabove-mentioned formula (I). Examples thereof include alkali metal saltssuch as sodium salt and potassium salt; alkaline earth metal salts suchas magnesium salt and calcium salt; ammonium salt; organic base saltssuch as trimethylamine salt, triethylamine salt, pyridine salt, pycolinesalt, dicyclohexylamine salt and N,N'-dibenzylethylenediamine salt; andamino acid salts such as lysine salt and arginine salt.

The compound of the present invention has superior hypoglycemic actionand hypolipidemic action, and is not only useful as an agent for theprevention and treatment of diabetes and hyperlipidemia, but alsoexpected to be useful as an agent for preventing arteriosclerosis. Whenthe compound of the formula (I), which is the compound of the presentinvention, or a pharmaceutically acceptable salt thereof is used as apharmaceutical preparation, it is generally admixed with apharmacologically acceptable carrier, excipient, diluent, extender,disintegrant, stabilizer, preservative, buffer, emulsifier, aromatic,coloring, sweetener, thickener, flavor, solubilizer, and other additivesknown per se, such as water, vegetable oil, alcohol such as ethanol andbenzyl alcohol, carbohydrate such as polyethylene glycol, glyceroltriacetate, gelatin, lactose and starch, magnesium stearate, talc,lanolin, petrolatum and the like, and formulated into tablet, pill,powder, granule, suppository, injection, eye drop, liquid, capsule,troche, aerosol, elixir, suspension, emulsion, syrup and the like whichmay be administered orally or parenterally. While the dose variesdepending on the kind and severity of the disease, the compound to beadministered, administration route, age, sex and body weight of patientand the like, the compound (I) is preferably administered orally at adose of, in general, 0.01-1,000 mg, particularly 0.05-100 mg per day toan adult.

The compound of the formula (I) has one or more asymmetric carbons. Whenit has one asymmetric carbon, a pure optically active compound, amixture thereof at an optional proportion or a racemate exists; and whenit has two or more asymmetric carbons, optically pure diastereomers,racemates thereof, a combination of these or a mixture thereof at anoptional proportion exist(s). These are all encompassed in the presentinvention. Depending on the case, they may be hydrates. As is evidentfrom the structure, the above-mentioned compound (I) can exist as aketo-enol type tautomer, which is also within the scope of the presentinvention.

The compound of the present invention can be synthesized, for example,by the following methods. It is needless to say that the productionmethod of the compound of the present invention is not limited to them.##STR6##

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Step 1

The compound (III) wherein R₆₁ is a carboxy-protecting group such asbenzyl, R₅₁ is a lower alkyl, an optionally substituted aromatichydrocarbon, an optionally substituted alicyclic hydrocarbon, anoptionally substituted heterocyclic group, an optionally substitutedcondensed heterocyclic group or a group of the formula ##STR7## whereinR₁, R₂ and R₃ are as defined above, and R₄ and R₅ are as defined above,can be synthesized by reacting compound (II) wherein R₄ and R₆₁ are asdefined above, which is an aspartate derivative, in the presence ofpyridine or a base such as triethylamine, in acid anhydride such asacetic anhydride and propionic anhydride, at room temperature toheating, and treating the resulting compound with water. In thisreaction, addition of 4-dimethylaminopyridine sometimes affords betterresults.

Step 2

The compound (IV) wherein R₆ is an alkyl, and R₄ and R₅ are as definedabove, is obtained by removing N-acyl such as N-acetyl of the formulaR₅₁ --CO-- by heating compound (III) wherein R₄, R₅, R₅₁ and R₆₁ are asdefined above, in an acidic solvent such as hydrochloric acid. Since R₆is eliminated at the same time, the resulting compound is esterified byreacting same in an alcohol solvent such as methanol, ethanol andpropanol, in the presence of an acid such as hydrogen chloride, wherebycompound (IV) is obtained.

Step 3

The compound (VI) wherein R, R₄, R₅ and R₆ are as defined above, can besynthesized by reacting compound (IV) wherein R₄, R₅ and R₆ are asdefined above, and compound (V) wherein Y is a halogen atom and R is asdefined above, in an organic solvent such as benzene, toluene,dichloromethane, chloroform, ether, dioxane, tetrahydrofuran,acetonitrile, dimethoxyethane, pyridine and acetone or a mixed solventthereof, in the presence of a base such as triethylamine, pyridine andN-methylmorpholine under cooling to room temperature.

Step 4

The compound (VII) wherein R, R₄, R₅ and R₆ are as defined above, can besynthesized by reacting compound (VI) wherein R, R₄, R₅ and R₆ are asdefined above, in an organic solvent such as benzene, toluene,acetonitrile, chloroform and tetrahydrofuran, or without solvent, in thepresence of an acid catalyst such as sulfuric acid and p-toluenesulfonicacid and a dehydrating agent such as acetic anhydride, at roomtemperature to under heating, preferably under heating.

Step 5

The compound (VIII) wherein R, R₄ and R₅ are as defined above, can besynthesized by reducing compound (VII) wherein R, R₄, R₅ and R₆ are asdefined above, by a conventional method, using a reducing agent such asdiisobutyl aluminum hydride, in an organic solvent such as benzene,toluene, ether, dioxane and tetrahydrofuran.

Step 6

The compound (IX) wherein Z is p-toluenesulfonyloxy, benzenesulfonyloxy,methanesulfonyloxy or a leaving group such as halogen atom and the like,and R, R₄ and R₅ are as defined above, can be synthesized by reactingcompound (VIII) wherein R, R₄ and R₅ are as defined above, and sulfonylchloride such as p-toluenesulfonyl chloride, benzenesulfonyl chlorideand methanesulfonyl chloride, or a halogenating agent such as phosphorustribromide and thionyl chloride, in an organic solvent such as benzene,toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran,acetonitrile, dimethylformamide, dimethylsulfoxide, acetone and ethylacetate, or a mixed solvent thereof, or without solvent, in the presenceof a base such as triethylamine, 4-dimethylaminopyridine and pyridine,under cooling to under heating.

Step 7

The compound (XI) wherein R, R₄ and R₅ are as defined above, can besynthesized by reacting compound (IX) wherein R, R₄, R₅ and Z are asdefined above, and 4-hydroxybenzaldehyde (X) in an organic solvent suchas benzene, toluene, dichloromethane, chloroform, ether, dioxane,tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide,sulforan and dimethoxyethane, in the presence of a base such as sodiumhydride, potassium hydride, sodium amide, sodium alkoxide, potassiumalkoxide, triethylamine and sodium hydroxide, under cooling to underheating.

Step 8

The compound (XII) wherein R, R₄ and R₅ are as defined above can besynthesized by reducing compound (XI) wherein R, R₄ and R₅ are asdefined above, using a catalyst such as sodium borohydride, lithiumaluminum hydride, lithium borohydride and dibutyl aluminum hydride, in asolvent such as ethanol and isopropanol.

Step 9

The compound (XIII) wherein R, R₄, R₅ and Y are as defined above, can besynthesized by reacting compound (XII) wherein R, R₄ and R₅ are asdefined above, in a solvent such as pyridine and dioxane in the presenceor absence of a catalyst such as zinc chloride, adding a halogenatingagent such as hydrogen bromide, phosphorus trichloride, phosphorustribromide and thionyl chloride, at room temperature to under heating.It can be also synthesized by reacting compound (XII) wherein R, R₄ andR₅ are as defined above, in a solvent such as anhydrous carbontetrachloride, adding triphenylphosphine, at room temperature to underheating.

Step 10

The compound (XIV) wherein R₇ is a lower alkyl, and R, R₄ and R₅ are asdefined above, can be synthesized by reacting compound (XIII) wherein R,R₄, R₅ and Y are as defined above, with malonic diester, in an organicsolvent such as benzene, toluene, dichloromethane, chloroform, ether,dioxane, tetrahydrofuran, acetonitrile, dimethylformamide,dimethylsulfoxide, sulforan and dimethoxyethane, in the presence of abase such as sodium hydride, potassium hydride, sodium amide, sodiumalkoxide, potassium alkoxide, triethylamine and sodium hydroxide, undercooling to under heating.

Step 11

The compound (I) wherein R, R₄ and R₅ are as defined above, can besynthesized by reacting compound (XIV) wherein R, R₄, R₅ and R₇ are asdefined above, with hydroxyamine in an anhydrous alcohol solution, undercooling to under heating.

When the compound has hydroxy as the substituent for R, a compoundhaving methoxy and the like as the substituent is synthesized andhydrolyzed under acidic conditions.

The compound (VIII) can be synthesized by introducing substituent R₁after ring closure, as mentioned below.

Step 12

The compound (XVI) wherein R₂, R₃, R₄, R₅, R₆ and Y are as definedabove, can be synthesized by reacting compound (IV) wherein R₄, R₅ andR₆ are as defined above, with compound (XV) wherein R₂, R₃ and Y are asdefined above, in an organic solvent such as benzene, toluene,dichloromethane, chloroform, ether, dioxane, tetrahydrofuran,acetonitrile, dimethoxyethane, pyridine and acetone, or a mixed solventthereof, in the presence of a base such as triethylamine, pyridine andN-methylmorpholine, under cooling to room temperature.

Step 13

The compound (XVII) wherein R₂, R₃, R₄, R₅, R₆ and Y are as definedabove, can be synthesized by reacting compound (XVI) wherein R₂, R₃, R₄,R₅, R₆ and Y are as defined above, in an organic solvent such asbenzene, toluene, acetonitrile, chloroform and tetrahydrofuran orwithout solvent, in the presence of an acid catalyst such as sulfuricacid and p-toluenesulfonic acid and a dehydrating agent such as aceticanhydride, at room temperature to under heating, preferably underheating.

Step 14

The compound (XVIII) wherein R₂, R₃, R₄, R₅ and Y are as defined above,can be synthesized by reducing compound (XVII) wherein R₂, R₃, R₄, R₅and Y are as defined above, in an organic solvent such as benzene,toluene, ether, dioxane and tetrahydrofuran, using a reducing agent suchas diisobutyl aluminum hydride, by a conventional method.

Step 15

The compound (VIII) wherein R, R₄ and R₅ are as defined above, can besynthesized by reacting compound (XVIII) wherein R₂, R₃, R₄, R₅ and Yare as defined above, and compound (XIX) wherein R₁ and X are as definedabove, in an organic solvent such as benzene, toluene, dichloromethane,chloroform, ether, dioxane, tetrahydrofuran, acetonitrile,dimethylformamide and dimethylsulfoxide, water or a mixed solventthereof, in the presence of a base such as sodium hydride, potassiumhydride, sodium amide, sodium alkoxide, potassium alkoxide,triethylamine and sodium hydroxide, under cooling to under heating.

The compound (VI) can be also synthesized by the following steps.

Step 16

The compound (VI) wherein R, R₄, R₅ and R₆ are as defined above, can besynthesized by reacting compound (XVI) wherein R₂, R₃, R₄, R₅, R₆ and Yare as defined above, and compound (XIX) wherein R₁ and X are as definedabove, in an organic solvent such as benzene, toluene, dichloromethane,chloroform, ether, dioxane, tetrahydrofuran, acetonitrile,dimethylformamide and dimethylsulfoxide, water or a mixed solventthereof, in the presence of a base such as sodium hydride, potassiumhydride, sodium amide, sodium alkoxide, potassium alkoxide,triethylamine and sodium hydroxide, under cooling to under heating.

Step 17

The compound (VII) wherein R, R₄, R₅ and R₆ are as defined above, can besynthesized by reacting compound (III) wherein R₄, R₅, R₅₁ and R₆₁ areas defined above, in an organic solvent such as benzene, toluene,acetonitrile, chloroform and tetrahydrofuran or without solvent, in thepresence of an acid catalyst such as sulfuric acid and p-toluenesulfonicacid and a dehydrating agent such as acetic anhydride, at roomtemperature to under heating, preferably under heating.

Step 18

The compound (XXI) wherein R, R₄, R₅ and R₇ are as defined above, can besynthesized by refluxing under heating compound (XI) wherein R, R₄ andR₅ are as defined above, and compound (XX) wherein R₇ is as definedabove, in an organic solvent such as toluene and benzene, using acatalyst such as piperidinium acetate, ethylene diammonium acetate andammonium acetate, which has been formed from acetic acid and piperidinein the system, while removing water out from the system.

Step 19

The compound (XIV) wherein R, R₄, R₅ and R₇ are as defined above can besynthesized by reacting compound (XXI) wherein R, R₄, R₅ and R₇ are asdefined above, in an organic solvent such as methanol, ethanol,propanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane andacetic acid or a mixed solvent thereof, using a catalyst such aspalladium carbon and palladium black under a hydrogen atmosphere atnormal temperature to under heating.

Step 20

The compound (XXII) wherein R, R₄, R₅ and Y are as defined above, can besynthesized by hydrolyzing compound (XIV) wherein R, R₄, R₅ and R₇ areas defined above, to give a dicarboxylic acid and treating same with ahalogenating reagent such as thionyl chloride and oxalyl chloride.

Step 21

The compound (I') wherein R, R₄ and R₅ are as defined above can besynthesized by reacting compound (XXII) wherein R, R₄, R₅ and Y are asdefined above, with hydroxyl amine, in the presence of a base such aspyridine and triethylamine.

The above-mentioned methods are particularly advantageous when P and Qare hydrogen atoms.

The compound (I) thus obtained can be isolated and purified by knownseparation-purification means such as concentration, concentration underreduced pressure, solvent extraction, precipitation, recrystallizationand chromatography.

Of the compounds (I), a compound wherein P and Q are combined, which isrepresented by the formula (I') ##STR8## wherein R, R₄ and R₅ are asdefined above, can be synthesized by, for example, the following method.##STR9## Step 22

The compound (XXI) wherein R, R₄, R₅ and R₇ are as defined above, can besynthesized by reacting compound (IX) wherein R, R₄, R₅ and Z are asdefined above, with compound (XX) wherein R₇ is as defined above, in anorganic solvent such as benzene, toluene, dichloromethane, chloroform,ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide,dimethylsulfoxide, sulforan and dimethoxyethane, in the presence of abase such as sodium hydride, potassium hydride, sodium amide, sodiumalkoxide, potassium alkoxide, triethylamine and sodium hydroxide, undercooling to under heating.

Step 23

The compound (I') wherein R, R₄ and R₅ are as defined above, can besynthesized by reacting compound (XXI) wherein R, R₄, R₅ and R₇ are asdefined above, with hydroxyamine using sodium methoxide in an anhydrousmethanol solution, under cooling to under heating.

The present invention is explained in more detail by way of Examples inthe following, to which the present invention is not limited.

EXAMPLE 1

Step 1: Synthesis of benzyl 3-acetamido-4-oxopentanoate

β-Benzyl L-aspartate (400 g, 1.79 mol) was suspended in triethylamine(748 ml, 5.37 mol) and acetic anhydride (676 ml, 7.16 mol) was dropwiseadded at 0° C. with stirring. After stirring for 30 minutes,4-dimethylaminopyridine (20.0 g, 0.16 mol) was portionwise added underice-cooling. The mixture was stirred overnight at room temperature, andice was added under ice-cooling. At the end of the exothermic process,water (700 ml) was added. A 7.5N aqueous solution of potassium hydroxidewas portionwise added to make its pH 9. The mixture was extracted threetimes with ethyl acetate (1,000 ml), and the organic layer was washedtwice with 1N hydrochloric acid (1,000 ml), twice with a saturatedaqueous solution of sodium hydrogencarbonate (500 ml) and with saturatedbrine (500 ml) in order. The layer was dried over magnesium sulfate andconcentrated to dryness to give 390 g of the title compound.

Step 2: Synthesis of methyl 3-amino-4-oxopentanoate hydrochloride

6N Hydrochloric acid (700 ml) was added to the compound (390 g, 1.50mol) synthesized in the above Step 1, and the mixture was stirred underreflux for 2 hours. The mixture was cooled to room temperature and thereaction mixture was washed twice with dichloromethane (500 ml). Theaqueous layer was concentrated to dryness. A solution of hydrogenchloride in methanol (1,500 ml) was added under ice-cooling and themixture was stirred. The mixture was gradually warmed and the mixturewas stirred overnight at room temperature. Concentration to dryness gave247 g of a crude product. The crude product (60 g) was recrystallizedfrom isopropanol to give 30 g of the title compound as a white solid.

Step 3: Synthesis of methyl 3-(benzene-2-carboxamide)-4-oxopentanoate

The compound (9.40 g, 51.3 mmol) synthesized in the above Step 2 wassuspended in dichloromethane (200 ml) at 0° C. Benzoyl chloride wasadded thereto, and N-methylmorpholine (20.8 g, 0.2 mol) was dropwiseadded gradually with stirring. The mixture was stirred for 3.5 hours,and water (100 ml) was added to separate an organic layer. Further, anorganic layer was extracted from the aqueous layer with dichloromethane(100 ml). The extracted organic layers were combined, washed with 1Naqueous hydrochloric acid (100 ml) and water (100 ml) in order, anddried over magnesium sulfate. Concentration to dryness gave 12.75 g ofthe title compound (yield 100%).

Step 4: Synthesis of methyl 2-(2-phenyl)-5-methyl-4-oxazolyl!acetate

Anhydrous acetate (70 ml) was added to the compound (12.75 g, 51.2 mmol)synthesized in the above Step 3 and the compound was dissolved. Con.sulfuric acid (1.0 ml) was dropwise added with stirring. The mixture wasstirred at 90° C. for 3 hours and cooled to room temperature. Water (100ml) was added to the reaction mixture, and the mixture was neutralizedwith a saturated aqueous solution of sodium hydrogencarbonate, andextracted with dichloromethane (100 ml). The extract was dried overmagnesium sulfate, and concentrated to dryness to give 8.75 g of thetitle compound (yield 74%).

Step 5: Synthesis of 2- 2-(2-phenyl)-5-methyl-4-oxazolyl!ethanol

A solution of the compound (8.75 g, 37.88 mmol) synthesized in the aboveStep 4 in toluene (200 ml) was dropwise added to a solution (133 ml,133.20 mmol) of diisobutyl aluminum hydride in toluene at 0° C. under anitrogen stream. Two hours later, methanol (100 ml) was dropwlse added.Then, 2N hydrochloric acid (700 ml) was added to this gel reactionmixture to dissolve same, and the mixture was extracted 4 times withethyl acetate (500 ml). The extracted organic layers were combined,washed with saturated brine (200 ml) and dried over magnesium sulfate.Concentration to dryness gave 7.69 g of the title compound (yield 100%).

Step 6: Synthesis of 2-2-(2-phenyl)-5-methyl-4-oxazolyl!-1-ethyltosylate

Pyridine (30 ml) was added to a solution (15 ml) of the compound (7.69g, 37.88 mmol) synthesized in the above Step 5 in dichloromethane, andp-toluenesulfonyl chloride (7.58 g, 39.77 mmol) was gradually added at0° C. After stirring for 6 hours, dichloromethane (100 ml) was added todilute same, and dilute hydrochloric acid (100 ml) was added. Themixture was partitioned, and the organic layer was sequentially washedwith water (100 ml), a saturated aqueous solution of sodiumhydrogencarbonate (100 ml) and saturated brine (100 ml). Drying overmagnesium sulfate and concentration to dryness gave 11.63 g of the titlecompound (yield 86%).

Step 7: Synthesis of 4- 2-2-(2-phenyl)-5-methyl-4-oxazolyl!ethoxy!benzaldehyde

A 60% oil of sodium hydride (3.14 g, 78.4 mmol) was washed twice withn-hexane (20 ml) under a nitrogen stream and added withdimethylformamide (20 ml), and the mixture was cooled to 0° C. Asolution (20 ml) of 4-hydroxyaldehyde (9.57 g, 78.4 mmol) indimethylformamide was added with stirring. After stirring for 10minutes, a solution (30 ml) of the compound (28 g, 78.4 mmol)synthesized in the above Step 6 in dimethylformamide was dropwise added.The mixture was warmed to room temperature and stirred for 60 hours. Themixture was neutralized with 1N hydrochloric acid and extracted twicewith ethyl acetate (100 ml). The extracted organic layer was washedtwice with water (100 ml) and dried over magnesium sulfate. The solventwas distilled away to give 24.1 g of the title compound as a colorlesssolid (yield 100%).

Step 8: Synthesis of 4- 2-2-(2-phenyl)-5-methyl-4-oxazolyl!ethoxy!benzyl alcohol

Sodium borohydride (2.46 g, 65.1 mmol) was gradually added to a solution(300 ml) of the compound (20 g, 65.1 mmol) synthesized in the above Step7 in ethanol, and the mixture was stirred for 1 hour. Ethanol wasdistilled away and water (200 ml) was added. Filtration of the resultingprecipitates gave 19.5 g of the title compound as a yellow solid (yield97%).

Step 9: Synthesis of 4- 2-2-(2-phenyl)-5-methyl-4-oxazolyl!ethoxy!benzyl chloride

Thionyl chloride (8.9 ml, 124.2 mmol) was gradually added to a solution(300 ml) of the compound (19.18 g, 62.1 mmol) synthesized in the aboveStep 8 and zinc chloride (1.74 g, 12.78 mmol) in dioxane at roomtemperature, and the mixture was stirred for 1 hour. After stirring,dioxane and thionyl chloride were distilled away under reduced pressureand water (200 ml) was added. The mixture was extracted twice withdichloromethane (100 ml) and dried over magnesium sulfate. After drying,the solvent was distilled away to give 19.69 g of the title compound asa yellow solid (yield 94%).

Step 10: Synthesis of diethyl 4- 2-2-(2-phenyl)-5-methyl-4-oxazolyl!ethoxy!benzyl malonate

A 60% oil of sodium hydride (488 mg, 12.2 mmol) was washed twice withn-hexane (5ml) under a nitrogen stream and added with tetrahydrofuran(20 ml), and the mixture was cooled to 0° C. Diethyl malonate (1.95 g,12.2 mmol) was added with stirring. After stirring for 30 minutes, thecompound (4 g, 12.2 mmol) synthesized in the above Step 9 was added andthe mixture was heated at 70° C. for 2 hours. The mixture was warmed toroom temperature and the mixture was neutralized with 1N hydrochloricacid. The mixture was extracted twice with dichloromethane (100 ml) anddried over magnesium sulfate. The solution was purified by fast flowliquid chromatography (developing solvent; hexane:ethyl acetate=2:1) togive 3.13 g of the title compound as a colorless solid (yield 57%).

Step 11: Synthesis of 4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzyl!-3,5-isoxazolidinedione

A solution (4 ml) of hydroxyamine.hydrochloride (348 mg, 5.00 mmol) inanhydrous methanol was added to a solution (4 ml) of sodium methoxide(540 mg, 9.99 mmol) in anhydrous methanol at 0° C. The resulting sodiumchloride was filtered off and a solution (4 ml) of the compound (1.5 g,3.33 mol) synthesized in the above Step 10 in anhydrous methanol wasadded. The mixture was stirred overnight at room temperature. Afterstirring, the solvent was distilled away, and the residue was dissolvedin an aqueous solution of sodium hydroxide and washed twice with ether(20 ml). 1N Hydrochloric acid was added to aqueous layer to make sameacidic. The mixture was extracted twice with ether (50 ml), dried overmagnesium sulfate. The obtained solid was dissolved in ether and aninsoluble material was removed. Evaporation of ether under reducedpressure gave 412 mg of the title compound as a colorless solid (yield32%).

EXAMPLE 1'

Synthesis of dimethyl 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzilidene malonate (Step 18)

Dimethyl malonate (1.39 g, 0.01 mol), acetic acid (0.3 ml) andpiperidine (0.3 ml) were added to a solution of the compound (2.94 g,0.01 mol) synthesized in Example 1, Step 7 in toluene (30 ml), and themixture was refluxed under heating using a Dean Stark trap whileremoving water to outside the system. Four hours later, toluene wasdistilled away and the obtained residue was recrystallized from methanolto give a colorless solid (2.5 g, yield 60%).

Synthesis of dimethyl 4- 2-2-(2-phenyl)-5-methyl-4-oxazolyl!ethoxy!benzyl malonate (Step 19)

The above-mentioned compound (2.5 g, 0.06 mol) was dissolved in a mixedsolvent of methanol-dioxane (1:5, 20 ml), and 5% Pd-C (150 mg) wasadded. The mixture was vigorously stirred under an H₂ atmosphere atnormal temperature and under atmospheric pressure. Two hours later, thecatalyst was filtered off and the solvent was distilled away to give asolid. Recrystallization from methanol gave a colorless solid (2.15 g,yield 85%).

Synthesis of 4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzyl!-3,5-isoxazolidinedione(Step 11)

A solution (4 ml) of sodium methoxide (574 mg, 10.6 mmol) in anhydrousmethanol was gradually added to hydroxyamine.hydrochloride (360 mg, 5.3mmol) in anhydrous methanol solvent (4 ml). The precipitated sodiumchloride was filtered off, and a solution (4 ml) of the above-mentionedcompound (1.5 g, 3.5 mmol) in anhydrous methanol was added. The mixturewas stirred at 60° C. for 3 hours.

The solvent was distilled away, and 1N aqueous HCl (50 ml) was added tothe residue to make same assume acidity. The residue was extracted twicewith ether (50 ml) and dried over magnesium sulfate. The solvent wasdistilled away and the obtained solid was recrystallized twice frommethanol to give 650 mg of a colorless solid (yield 47%).

mp: 154.6-155.4° C.

The signals at 400 MHz NMR: 2.35 (s,3H), 2.92 (t,J=6.5 Hz,2H), 3.23-3.27(m,2H), 3.50 (t,J=4.9 Hz,1H), 4.11 (t,J=6.7 Hz,2H), 6.77-7.95 (m,9H)

Reference Example 1

Synthesis of diethyl 4-hydroxybenzilidene malonate

4-Hydroxybenzaldehyde (24.4 g, 0.20 mol), diethyl malonate (30.4 ml, 0.2mol), benzoic acid (3.0 g) and piperidine (3.0 ml) were dissolved intoluene (200 ml), and the mixture was refluxed for 6 hours withdehydration using a Dean Stark trap. After cooling the mixture to roomtemperature, the resulting solid was filtrated and washed with toluene,a 0.5N aqueous solution of citric acid, a saturated aqueous solution ofsodium hydrogencarbonate and ether in order. The obtained solid wasdried under reduced pressure to quantitatively give the title compoundas a white solid.

EXAMPLE 2

Step 22: Synthesis of diethyl 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzilidene malonate

A 60% oil of sodium hydride (616 mg, 15.4 mmol) was washed twice withn-hexane (2 ml) under a nitrogen stream and added with dimethylformamide(20 ml). The mixture was cooled to 0° C. Diethyl 4-hydroxybenzilidenemalonate (4.07 g, 15.4 mmol) synthesized in the above Reference Example1 was added to this solution. After stirring for 10 minutes, thecompound (5.00 g, 14.0 mmol) synthesized in Example 1, Step 6 was addedand the mixture was stirred overnight. The reaction mixture wasextracted with ethyl acetate, and the extract was washed with water andsaturated brine. After the washing, the organic layer was dried overmagnesium sulfate and the solvent was distilled away under reducedpressure. The obtained residue was purified by silica gel columnchromatography (developing solvent; chloroform:methanol=98:2) to give5.44 g of the title compound as a white solid.

Step 23: Synthesis of 4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzilidene!-3,5-isoxazolidinedione

A solution (10 ml) of hydroxyamine.hydrochloride (977 mg, 14.1 mmol) inanhydrous methanol was added to a solution (10 ml) of sodium methoxide(956 mg, 14.1 mmol) in anhydrous methanol at 0° C. The resulting sodiumchloride was filtered off and a solution (10 ml) of the compound (4.21g, 9.37 mol) synthesized in the above Step 17 in anhydrous methanol wasadded. An equivalent of sodium methoxide was added, and the mixture wasstirred for 3 hours. After stirring, the solvent was distilled away, andthe residue was extracted with ethyl acetate, washed with dilutehydrochloric acid and saturated brine, and dried over magnesium sulfate.The solvent was distilled away. The obtained solid was dissolved inether and an insoluble material was removed. Ether was distilled awayunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (developing solvent; chloroform: methanol=95:5) togive 1.45 g of the title compound as a white solid (yield 32%).

EXAMPLES 3 AND 4

In the same manner as in Example 1, the compounds of Table 1 wereobtained.

                                      TABLE 1    __________________________________________________________________________                                     Melting    No.       Compound                      temp. .sup.1 H NMR (CDCl.sub.3 δ                                           value)    __________________________________________________________________________       1 #STR10##                    91.7˜ 94.2° C.                                           2.35(s, 3H), 2.92(t, J=6.5Hz, 2H),                                           3.01-3.70(m, 3H, 4.11(t, J=6.7Hz),                                           2H), 6.75-8.00(m, 9H)    1'       1 #STR11##                    154.6˜ 155.4° C.                                           2.35(s, 3H), 2.92(t, J=6.5Hz, 2H),                                           3.23-3.27(m, 2H), 3.50(t, J=4.0Hz,                                           1H), 4.11(t, J=6.7Hz, 2H),                                           6.77-7.95(m, 9H)    2       0 #STR12##                    151.2˜ 152.4° C.                                           2.37(s, 3H), 3.00(t, J=6.8Hz, 2H),                                           4.30(t, J=6.8Hz, 2H), 6.88(d,                                           J=8.8Hz, 2H), 7.41(m, 5H),                                           7.92(brs, 1H), 7.98(m, 2H),                                           8.07(s, 1H)    3       2 #STR13##                    114.0˜ 116.5° C.                                           2.37(s, 3H), 2.94(t, J=6.4Hz, 2H),                                           3.19-3.51(m, 3H), 4.15(t, J=6.4Hz,                                           2H), 6.78(d, J=8.6Hz, 2H), 7.13(d,                                           J=8.6Hz, 2H), 7.37(m, 2H), 7.82(m,                                           2H)    4       3 #STR14##                    100.0˜ 102.0° C.                                           1.68(t, J=7.1Hz, 3H), 2.21(s, 3H),                                           2.79(t, J=6.6Hz, 2H), 2.95(d,                                           J=7.8Hz, 2H), 3.49(t, J=7.8Hz,                                           1H), 4.08(t, J=6.6Hz, 2H), 5.22(q,                                           J=7.1Hz, 1H), 6.80(d, J=8.6Hz,                                           2H), 7.10(d, J=8.6Hz, 2H),                                           7.1-7.2(m, 1H), 7.32(m, 1H),                                           7.66(m, 1H), 8.46(m, 1H)                                           (DMSO-d.sub.6)    __________________________________________________________________________

As mentioned above, the present invention is not limited to theabove-mentioned Examples. For example, the compounds shown in thefollowing Tables 2 to 17 are also encompassed in the present invention.

                                      TABLE 2    __________________________________________________________________________    4 #STR15##    R              R.sub.4                     R.sub.5                       R          R.sub.4                                    R.sub.5                                      R          R.sub.4                                                   R.sub.5    __________________________________________________________________________     ##STR16##    5              H Me                       5 #STR17## H Me                                      5 #STR18## H Me    6 #STR19##     H Me                       6 #STR20## H Me                                      6 #STR21## H Me    7 #STR22##     H Me                       7 #STR23## H Me                                      7 #STR24## H Et    8 #STR25##     H Me                       8 #STR26## H Me                                      8 #STR27## H Et    9 #STR28##     H Et                       9 #STR29## H Me                                      9 #STR30## H Me    0 #STR31##     H Et                       0 #STR32## Et                                    Me                                      0 #STR33## H Me    1 #STR34##     H Et                       1 #STR35## Et                                    Et                                      1 #STR36## Me                                                   Me    2 #STR37##     H Et                       2 #STR38## H Me                                      2 #STR39## H Me    3 #STR40##     H Et                       3 #STR41## H Me                                      3 #STR42## H Me    4 #STR43##     Me                     Et                       4 #STR44## H Me                                      4 #STR45## H Me    __________________________________________________________________________

                                      TABLE 3    __________________________________________________________________________    4 #STR46##    R          R.sub.4                 R.sub.5                   R         R.sub.4                               R.sub.5                                 R         R.sub.4                                             R.sub.5    __________________________________________________________________________     ##STR47##    5          H Me                   5 #STR48##                             H Me                                 5 #STR49##                                           H Me    6 #STR50## H Me                   6 #STR51##                             H Me                                 6 #STR52##                                           H Me    7 #STR53## H Et                   7 #STR54##                             H Me                                 7 #STR55##                                           H Et    8 #STR56## H Me                   8 #STR57##                             H Me                                 8 #STR58##                                           H Et    9 #STR59## H Me                   9 #STR60##                             H Me                                 9 #STR61##                                           H Me    0 #STR62## H Me                   0 #STR63##                             Et                               Me                                 0 #STR64##                                           H Me    1 #STR65## H Me                   1 #STR66##                             Et                               Et                                 1 #STR67##                                           Me                                             Me    2 #STR68## H Me                   2 #STR69##                             H Me                                 2 #STR70##                                           H Me    3 #STR71## H Me                   3 #STR72##                             H Me                                 3 #STR73##                                           H Me    4 #STR74## Me                 Me                   4 #STR75##                             H Me                                 4 #STR76##                                           H Me    __________________________________________________________________________

                                      TABLE 4    __________________________________________________________________________    4 #STR77##    R         R.sub.4                R.sub.5                  R             R.sub.4                                  R.sub.5                                    R             R.sub.4                                                    R.sub.5    __________________________________________________________________________     ##STR78##    5         H Me                  5 #STR79##    H Me                                    5 #STR80##    H Me    6 #STR81##              H Me                  6 #STR82##    H Me                                    6 #STR83##    H Me    7 #STR84##              H Et                  7 #STR85##    H Me                                    7 #STR86##    H Et    8 #STR87##              H Me                  8 #STR88##    H Me                                    8 #STR89##     H                                                    Et    9 #STR90##              H Me                  9 #STR91##    H Me                                    9 #STR92##    H Me    0 #STR93##              H Me                  0 #STR94##    Et                                  Me                                    0 #STR95##    H Me    1 #STR96##              H Me                  1 #STR97##    Et                                  Et                                    1 #STR98##    Me                                                    Me    2 #STR99##              H Me                  2 #STR100##   H Me                                    2 #STR101##   H Me    3 #STR102##              H Me                  3 #STR103##   H Me                                    3 #STR104##   H Me    4 #STR105##              Me                Me                  4 #STR106##   H Me                                    4 #STR107##   H Me    __________________________________________________________________________

                                      TABLE 5    __________________________________________________________________________    4 #STR108##    R             R.sub.4                    R.sub.5                      R             R.sub.4                                      R.sub.5                                        R             R.sub.4                                                        R.sub.5    __________________________________________________________________________     ##STR109##    5             H Me                      5 #STR110##   H Me                                        5 #STR111##   H Me    6 #STR112##   H Me                      6 #STR113##   H Me                                        6 #STR114##   H Me    7 #STR115##   H Et                      7 #STR116##   H Me                                        7 #STR117##   H Et    8 #STR118##   H Me                      8 #STR119##   H Me                                        8 #STR120##    H                                                        Et    9 #STR121##   H Me                      9 #STR122##   H Me                                        9 #STR123##   H Me    0 #STR124##   H Me                      0 #STR125##   Et                                      Me                                        0 #STR126##   H Me    1 #STR127##   H Me                      1 #STR128##   Et                                      Et                                        1 #STR129##   Me                                                        Me    2 #STR130##   H Me                      2 #STR131##   H Me                                        2 #STR132##   H Me    3 #STR133##   H Me                      3 #STR134##   H Me                                        3 #STR135##   H Me    4 #STR136##   Me                    Me                      4 #STR137##   H Me                                        4 #STR138##   H Me    __________________________________________________________________________

                                      TABLE 6    __________________________________________________________________________    5 #STR139##    R.sub.1        X R.sub.2                       R.sub.3                         R.sub.4                           R.sub.5                             R.sub.1   X                                         R.sub.2                                           R.sub.3                                             R.sub.4                                               R.sub.5    __________________________________________________________________________     ##STR140##    6              S H Me                         H Me                             4 #STR141##                                       S H Me                                             H Me    5 #STR142##    S H Me                         H Me                             8 #STR143##                                       S H Me                                             H Me    6 #STR144##    S H Me                         H Me                             9 #STR145##                                       S H H H Et    7 #STR146##    S H H Me                           Me                             0 #STR147##                                       S H H Et                                               Et    8 #STR148##    S H H Me                           Et                             1 #STR149##                                       S H H Et                                               Me    9 #STR150##    S H H H Me                             2 #STR151##                                       S H H Et                                               Me    0 #STR152##    S H H H Me                             3 #STR153##                                       S H H H Me    1 #STR154##    S H Me                         H Me                             4 #STR155##                                       S H Me                                             H Me    2 #STR156##    S H Me                         H Me                             5 #STR157##                                       S H Me                                             H Me    3 #STR158##    S H Me                         H Me                             6 #STR159##                                       S H Me                                             H Me    __________________________________________________________________________

                                      TABLE 7    __________________________________________________________________________    5 #STR160##    R.sub.1        X R.sub.2                       R.sub.3                         R.sub.4                           R.sub.5                             R.sub.1    X                                          R.sub.2                                            R.sub.3                                              R.sub.4                                                R.sub.5    __________________________________________________________________________     ##STR161##    7              S H Me                         H Me                             4 #STR162##                                        S H Me                                              H Me    8 #STR163##    S H Me                         H Me                             9 #STR164##                                        S H Me                                              H Me    9 #STR165##    S H Me                         H Me                             6 #STR166##                                        S H H H Et    0 #STR167##    S H H Me                           Me                             7 #STR168##                                        S H H Et                                                Et    1 #STR169##    S H H Me                           Et                             8 #STR170##                                        S H H Et                                                Me    2 #STR171##    S H H H Me                             8 #STR172##                                        S H H Et                                                Me    3 #STR173##    S H H H Me                             0 #STR174##                                        S H H H Me    9 #STR175##    S H Me                         H Me                             1 #STR176##                                        S H Me                                              H Me    4 #STR177##    S H Me                         H Me                             2 #STR178##                                        S H Me                                              H Me    5 #STR179##    S H Me                         H Me                             9 #STR180##                                        S H Me                                              H Me    __________________________________________________________________________

                                      TABLE 8    __________________________________________________________________________    5 #STR181##    R.sub.1    X R.sub.2                   R.sub.3                     R.sub.4                       R.sub.5                         R.sub.1   X                                     R.sub.2                                       R.sub.3                                         R.sub.4                                           R.sub.5    __________________________________________________________________________     ##STR182##    3          S H Me                     H Me                         5 #STR183##                                   S H Me                                         H Me    9 #STR184##               S H Me                     H Me                         7 #STR185##                                   S H Me                                         H Me    6 #STR186##               S H Me                     H Me                         9 #STR187##                                   S H H H Et    7 #STR188##               S H H Me                       Me                         6 #STR189##                                   S H H Et                                           Et    8 #STR190##               S H H Me                       Et                         6 #STR191##                                   S H H Et                                           Me    1 #STR192##               S H H H Me                         8 #STR193##                                   S H H Et                                           Me    0 #STR194##               S H H H Me                         2 #STR195##                                   S H H H Me    2 #STR196##               S H Me                     H Me                         0 #STR197##                                   S H Me                                         H Me    3 #STR198##               S H Me                     H Me                         1 #STR199##                                   S H Me                                         H Me    4 #STR200##               S H Me                     H Me                         7 #STR201##                                   S H Me                                         H Me    __________________________________________________________________________

                                      TABLE 9    __________________________________________________________________________    5 #STR202##    R.sub.1       X R.sub.2                      R.sub.3                        R.sub.4                          R.sub.5                            R.sub.1  X                                       R.sub.2                                         R.sub.3                                           R.sub.4                                             R.sub.5    __________________________________________________________________________     ##STR203##    8             S H Me                        H Me                            6 #STR204##                                     S H Me                                           H Me    9 #STR205##   S H Me                        H Me                            8 #STR206##                                     S H Me                                           H Me    1 #STR207##   S H Me                        H Me                            2 #STR208##                                     S H H H Et    0 #STR209##   S H H Me                          Me                            5 #STR210##                                     S H H Et                                             Et    2 #STR211##   S H H Me                          Et                            6 #STR212##                                     S H H Et                                             Me    1 #STR213##   S H H H Me                            7 #STR214##                                     S H H Et                                             Me    2 #STR215##   S H H H Me                            1 #STR216##                                     S H H H Me    3 #STR217##   S H Me                        H Me                            9 #STR218##                                     S H Me                                           H Me    4 #STR219##   S H Me                        H Me                            8 #STR220##                                     S H Me                                           H Me    5 #STR221##   S H Me                        H Me                            3 #STR222##                                     S H Me                                           H Me    __________________________________________________________________________

                                      TABLE 10    __________________________________________________________________________    5 #STR223##    R.sub.1        X R.sub.2                       R.sub.3                         R.sub.4                           R.sub.5                             R.sub.1    X                                          R.sub.2                                            R.sub.3                                              R.sub.4                                                R.sub.5    __________________________________________________________________________     ##STR224##    6              O H Me                         H Me                             4 #STR225##                                        O H Me                                              H Me    5 #STR226##    O H Me                         H Me                             8 #STR227##                                        O H Me                                              H Me    6 #STR228##    O H Me                         H Me                             9 #STR229##                                        O H H H Et    7 #STR230##    O H H Me                           Me                             0 #STR231##                                        O H H Et                                                Et    8 #STR232##    O H H Me                           Et                             1 #STR233##                                        O H H Et                                                Me    9 #STR234##    O H H H Me                             2 #STR235##                                        O H H Et                                                Me    0 #STR236##    O H H H Me                             3 #STR237##                                        O H H H Me    1 #STR238##    O H Me                         H Me                             4 #STR239##                                        O H Me                                              H Me    2 #STR240##    O H Me                         H Me                             5 #STR241##                                        O H Me                                              H Me    3 #STR242##    O H Me                         H Me                             6 #STR243##                                        O H Me                                              H Me    __________________________________________________________________________

                                      TABLE 11    __________________________________________________________________________    5 #STR244##    R.sub.1        X R.sub.2                       R.sub.3                         R.sub.4                           R.sub.5                             R.sub.1    X                                          R.sub.2                                            R.sub.3                                              R.sub.4                                                R.sub.5    __________________________________________________________________________     ##STR245##    7              O H Me                         H Me                             4 #STR246##                                        O H Me                                              H Me    8 #STR247##    O H Me                         H Me                             9 #STR248##                                        O H Me                                              H Me    9 #STR249##    O H Me                         H Me                             6 #STR250##                                        O H H H Et    0 #STR251##    O H H Me                           Me                             7 #STR252##                                        O H H Et                                                Et    1 #STR253##    O H H Me                           Et                             8 #STR254##                                        O H H Et                                                Me    2 #STR255##    O H H H Me                             8 #STR256##                                        O H H Et                                                Me    3 #STR257##    O H H H Me                             0 #STR258##                                        O H H H Me    9 #STR259##    O H Me                         H Me                             1 #STR260##                                        O H Me                                              H Me    4 #STR261##    O H Me                         H Me                             2 #STR262##                                        O H Me                                              H Me    5 #STR263##    O H Me                         H Me                             9 #STR264##                                        O H Me                                              H Me    __________________________________________________________________________

                                      TABLE 12    __________________________________________________________________________    5 #STR265##    R.sub.1    X R.sub.2                   R.sub.3                     R.sub.4                       R.sub.5                         R.sub.1   X                                     R.sub.2                                       R.sub.3                                         R.sub.4                                           R.sub.5    __________________________________________________________________________     ##STR266##    3          O H Me                     H Me                         5 #STR267##                                   O H Me                                         H Me    9 #STR268##               O H Me                     H Me                         7 #STR269##                                   O H Me                                         H Me    6 #STR270##               O H Me                     H Me                         9 #STR271##                                   O H H H Et    7 #STR272##               O H H Me                       Me                         6 #STR273##                                   O H H Et                                           Et    8 #STR274##               O H H Me                       Et                         6 #STR275##                                   O H H Et                                           Me    1 #STR276##               O H H H Me                         8 #STR277##                                   O H H Et                                           Me    0 #STR278##               O H H H Me                         2 #STR279##                                   O H H H Me    2 #STR280##               O H Me                     H Me                         0 #STR281##                                   O H Me                                         H Me    3 #STR282##               O H Me                     H Me                         1 #STR283##                                   O H Me                                         H Me    4 #STR284##               O H Me                     H Me                         7 #STR285##                                   O H Me                                         H Me    __________________________________________________________________________

                                      TABLE 13    __________________________________________________________________________    1 #STR286##    R.sub.1        X R.sub.2                       R.sub.3                         R.sub.4                           R.sub.5                             R.sub.1  X R.sub.2                                          R.sub.3                                            R.sub.4                                              R.sub.5    __________________________________________________________________________     ##STR287##    2              O H Me                         H Me                             3 #STR288##                                      O H Me                                            H Me    4 #STR289##    " " " " "                             5 #STR290##                                      " " " " "    6 #STR291##    " " " " "                             7 #STR292##                                      " " H " Et    8 #STR293##    " " H Me                           "                             9 #STR294##                                      " " " Et                                              "    0 #STR295##    " " " " Et                             1 #STR296##                                      " " " " Me    2 #STR297##    " " " H Me                             3 #STR298##                                      " " " " "    4 #STR299##    " " " " "                             5 #STR300##                                      " " " H "    6 #STR301##    " " Me                         " "                             7 #STR302##                                      " " Me                                            " "    8 #STR303##    " " " " "                             9 #STR304##                                      " " " " "    0 #STR305##    " " " " "                             1 #STR306##                                      " " " " "    __________________________________________________________________________

                                      TABLE 14    __________________________________________________________________________    1 #STR307##    R.sub.1        X  R.sub.2                        R.sub.3                          R.sub.4                            R.sub.5                              R.sub.1   X  R.sub.2                                             R.sub.3                                               R.sub.4                                                 R.sub.5    __________________________________________________________________________     ##STR308##    2              NH H Me                          H Me                              3 #STR309##                                        NH H Me                                               H Me    4 #STR310##    "  " " " "                              5 #STR311##                                        "  " " " "    6 #STR312##    "  " " " "                              7 #STR313##                                        "  " H " Et    8 #STR314##    "  " H Me                            "                              9 #STR315##                                        "  " " Et                                                 "    0 #STR316##    "  " " " Et                              1 #STR317##                                        "  " " " Me    2 #STR318##    "  " " H Me                              3 #STR319##                                        "  " " " "    4 #STR320##    "  " " " "                              5 #STR321##                                        "  " " H "    6 #STR322##    "  " Me                          " "                              7 #STR323##                                        "  " Me                                               " "    8 #STR324##    "  " " " "                              9 #STR325##                                        "  " " " "    0 #STR326##    "  " " " "                              1 #STR327##                                        "  " " " "    __________________________________________________________________________

                                      TABLE 15    __________________________________________________________________________    1 #STR328##    R.sub.1        X  R.sub.2                        R.sub.3                          R.sub.4                            R.sub.5                              R.sub.1   X  R.sub.2                                             R.sub.3                                               R.sub.4                                                 R.sub.5    __________________________________________________________________________     ##STR329##    2              NH H Me                          H Me                              3 #STR330##                                        NH H Me                                               H Me    4 #STR331##    "  " " " "                              5 #STR332##                                        "  " " " "    6 #STR333##    "  " " " "                              7 #STR334##                                        "  " H " Et    8 #STR335##    "  " H Me                            "                              9 #STR336##                                        "  " " Et                                                 "    0 #STR337##    "  " " " Et                              1 #STR338##                                        "  " " " Me    2 #STR339##    "  " " H Me                              3 #STR340##                                        "  " " " "    4 #STR341##    "  " " " "                              5 #STR342##                                        "  " " H "    6 #STR343##    "  " Me                          " "                              7 #STR344##                                        "  " Me                                               " "    8 #STR345##    "  " " " "                              9 #STR346##                                        "  " " " "    0 #STR347##    "  " " " "                              1 #STR348##                                        "  " " " "    __________________________________________________________________________

                                      TABLE 16    __________________________________________________________________________    1 #STR349##    R.sub.1        X  R.sub.2                        R.sub.3                          R.sub.4                            R.sub.5                              R.sub.1   X  R.sub.2                                             R.sub.3                                               R.sub.4                                                 R.sub.5    __________________________________________________________________________     ##STR350##    2              NH H Me                          H Me                              3 #STR351##                                        NH H Me                                               H Me    4 #STR352##    "  " " " "                              5 #STR353##                                        "  " " " "    6 #STR354##    "  " " " "                              7 #STR355##                                        "  " H " Et    8 #STR356##    "  " H Me                            "                              9 #STR357##                                        "  " " Et                                                 "    0 #STR358##    "  " " " Et                              1 #STR359##                                        "  " " " Me    2 #STR360##    "  " " H Me                              3 #STR361##                                        "  " " " "    4 #STR362##    "  " " " "                              5 #STR363##                                        "  " " H "    6 #STR364##    "  " Me                          " "                              7 #STR365##                                        "  " Me                                               " "    8 #STR366##    "  " " " "                              9 #STR367##                                        "  " " " "    0 #STR368##    "  " " " "                              1 #STR369##                                        "  " " " "    __________________________________________________________________________

                                      TABLE 17    __________________________________________________________________________    1 #STR370##    R.sub.1        X  R.sub.2                        R.sub.3                          R.sub.4                            R.sub.5                              R.sub.1   X  R.sub.2                                             R.sub.3                                               R.sub.4                                                 R.sub.5    __________________________________________________________________________     ##STR371##    2              NH H Me                          H Me                              3 #STR372##                                        NH H Me                                               H Me    4 #STR373##    "  " " " "                              5 #STR374##                                        "  " " " "    6 #STR375##    "  " " " "                              7 #STR376##                                        "  " H " Et    8 #STR377##    "  " H Me                            "                              9 #STR378##                                        "  " " Et                                                 "    0 #STR379##    "  " " " Et                              1 #STR380##                                        "  " " " Me    2 #STR381##    "  " " H Me                              3 #STR382##                                        "  " " " "    4 #STR383##    "  " " " "                              5 #STR384##                                        "  " " H "    6 #STR385##    "  " Me                          " "                              7 #STR386##                                        "  " Me                                               " "    8 #STR387##    "  " " " "                              9 #STR388##                                        "  " " " "    0 #STR389##    "  " " " "                              1 #STR390##                                        "  " " " "    __________________________________________________________________________

Experimental Example 1

Genetically obese, hyperglycemic and hyperlipidemic diabetic mice(C57BL/Ksj-db/db, male, Jackson Laboratories/Clea Japan, Inc., 13 weeksof age and KK-Ay, male, Clea Japan, Inc., 13 weeks of age) were used forthe pharmacological tests. As a reference compound, a hypoglycemic agentCS-045 (±)-5-4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl!-2,4-thiazolidinedione!see Diabetes, vol. 37, p. 1549 (1988)! was used.

The mice were weighed and blood samples were taken immediately beforethe initiation of administration on day 1. Serum glucose and serumtriglyceride were measured, based on which the mice were grouped (6-8per group) in such a manner that there existed no difference in terms ofaverage body weight, average serum glucose and average serumtriglyceride.

The test drugs were all suspended in a solution of 0.5% sodiumcarboxymethylcellulose and administered orally twice a day (the secondadministration was 6 hours after the first administration) on day 1, day2, day 3 and day 4. To a vehicle control group, a solution of 0.5%sodium carboxymethylcellulose was orally administered.

At day 5, blood samples were taken again and measured for serum glucoseand serum triglyceride. The blood sample was taken from orbital cavityplexus by 400 μl under anesthetization with ether and kept at icetemperature. After separation into serum (12000 rpm, 5 min.), serumglucose was measured by hexokinase method (glucose-HK-test "BMY";Bohelinger Mannheim Yamanouchi) and serum triglyceride was measured byenzyme method (triglycolor III "BMY"; Bohelinger Mannheim Yamanouchi)using an automatic analyzer COBAS FARA (manufactured by Roche).

Change in percent of serum glucose and serum triglyceride in each groupwas calculated using serum glucose and serum triglyceride, respectively,of vehicle control group at day 5 as follows: ##EQU1## The results areshown in Table 18.

                  TABLE 18    ______________________________________    dose         serum glucose (%)                               serum triglyceride (%)    (mg/         KK-A.sup.γ                         db/db     KK-A.sup.γ                                         db/db    kg)          mouse   mouse     mouse mouse    ______________________________________    Ex. 1   10       -38.3   -19.8   -50.3 -29.1    CS-045  100      -29.4   -21.5   -22.9 -55.5    ______________________________________

As shown in Table 18, the compound of the present invention loweredserum glucose and serum triglyceride of both kinds of diabetic mice moresignificantly than did the control compound.

From the foregoing, it is evident that the compound of the presentinvention has superior hypoglycemic and hypolipidemic actions and isuseful for the treatment of diabetes and hyperlipidemia. In addition,the compound of the invention is expected to be efficacious for theprevention and treatment of the complications of diabetes.

INDUSTRIAL APPLICABILITY

The isoxazdidine derivative compound (I) and a salt thereof of thepresent invention are novel compounds having extremely potent and lowtoxic hypoglycemic action as compared with known oxazolidine derivativesand other therapeutic agents of diabetes, and are very useful astherapeutic agents for diabetes and hyperlipidemia. In addition, thecompounds of the present invention are expected to be useful for theprevention of the complications of diabetes, especially for theprevention of arteriosclerosis.

What is claimed is:
 1. A method for the treatment or prevention ofarteriosclerosis in a human, comprising administering to the human aneffective amount of an isoxazolidinedione compound of the formula (I)##STR391## wherein R is phenyl, biphenyl or naphthyl, which isoptionally substituted by 1 to 3 substituents; an alicyclic hydrocarbonhaving 3 to 7 carbon atoms, which is optionally substituted by 1 to 3substituents; an oxazolyl, isoxazolyl or 5-membered heterocyclic grouphaving 1 to 3 nitrogen atoms or 1 oxygen atom or 1 sulfur atom, which isoptionally substituted by 1 to 3 substituents; a 5-membered heterocyclicgroup having 1 to 3 nitrogen atoms or 1 oxygen atom or 1 sulfur atomwhich is condensed with a phenyl; or a group of the formula ##STR392##wherein R₁ is phenyl, biphenyl or naphthyl, which is optionallysubstituted by 1 to 3 substituents, an alicyclic hydrocarbon having 3 to7 carbon atoms, which is optionally substituted by 1 to 3 substituents,an oxazolyl, isoxazolyl or 5-membered heterocyclic group having 1 to 3nitrogen atoms which is optionally substituted by 1 to 3 substituents,or a heterocyclic group which is condensed with a phenyl; R₂ and R₃ arethe same or different and each is a hydrogen atom or a lower alkylhaving 1 to 4 carbon atoms, and X is an oxygen atom, a sulfur atom or asecondary amino;R₄ is a hydrogen atom or a lower alkyl having 1 to 4carbon atoms; R₅ is a lower alkyl having 1 to 4 carbon atoms; and P andQ are each a hydrogen atom or P and Q together form a bond,saidsubstituents being selected from the group consisting of hydroxyl, alower alkyl having 1 to 4 carbon atoms and a lower alkoxyl having 1 to 4carbon atoms; or a pharmaceutically acceptable salt thereof.
 2. Themethod of claim 1, wherein R₄ is a hydrogen atom and R₅ is a lower alkylhaving 1 to 4 carbon atoms, or a pharmaceutically acceptable saltthereof.
 3. The method of claim 2, wherein R is a phenyl optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhydroxyl, a lower alkyl having 1 to 4 carbon atoms and a lower alkoxylhaving 1 to 4 carbon atoms, or a pharmaceutically acceptable saltthereof.
 4. The method of claim 3, wherein R is phenyl, or apharmaceutically acceptable salt thereof.
 5. The method of claim 2,wherein R is a group of the formula ##STR393## or a pharmaceuticallyacceptable salt thereof.
 6. The method of claim 5, wherein R₁ is aphenyl optionally substituted by 1 to 3 substituents selected from thegroup consisting of hydroxyl, a lower alkyl having 1 to 4 carbon atomsand a lower alkoxyl having 1 to 4 carbon atoms, or a pharmaceuticallyacceptable salt thereof.
 7. The method of claim 1, wherein theisoxazolidinedione compound is administered in the form of apharmaceutical composition including a carrier.
 8. The method of claim1, wherein the isoxazolidinedione compound is selected from the groupconsisting of4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzyl!-3,5-isoxazolidinedione,and4- 4-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy!benzylidene!-3,5-isoxazolidinedione,ora pharmaceutically acceptable salt thereof.